Project 3: Role of Inflammation on Induction of Tau Pathology in the Brains of Transgenic IVIice Alzheimer disease (AD) impairs memory and causes cognitive and psychiatric deficits. The number of people with AD will quadruple to 115 million worldwide by 2050, with cumiulative costs of care in the absence of disease-modifying treatments exceeding $204rillion over the next 40 years alone in the USA. Should this expectation come to fruition, it will pose an unprecedented medical, social, and economic burden on our society. One of the most fundamental and unresolved questions in the field centers on elucidating the role that inflammation plays in disease progression, and in particular, how the cerebral buildup of p-amyloid (Ap) promotes inflammation and the development of hyperphosphorylated tau. Notably, our studies identified inflammation as an early and critical step that links Ap to tau pathology and cognitive decline. Supporting GWAS-derived evidence further reinforces the importance of inflammation, as single nucleotide polymorphisms in many immune-related genes significantly increase the probability of developing AD. Although inflammation is critical to disease progression, a detailed molecular analysis of specific mechanisms of the inflammatory response is greatly needed. Among numerous inflammatory pathways associated with AD, interleukin-ip (IL-ip) plays a critical pathogenic role. We hypothesize that AQ> alters intracellular protein clearance and trafficking, exacerbating IL-ip-mediated inflammation, eliciting tau pathology and synaptic and cognitive deficits. Our goal is to elucidate the impact of Ap on IL-ip signaling with emphasis on fiie relevance of protein clearance for IL-ip synthesis and protein trafficking for IL-1 receptor 1 (IL-1 Rl) levels. We developed several new and exciting transgenic models and viral approaches that add significantly to the field and enable us to dissect the molecular pathways by which Ap, IL-ip and tau interact and the mechanisms by which they adversely impact cognition during different stages of the disease process. Because a better understanding of these pathways is critical not only for academic reasons but also for helping to identify novel drug targets, the translational impact of this work is quite significant. RELEVANCE (See instructions): Inflammation plays both a protective and damaging role in Alzheimer disease (AD), so to identify a long lasting and effective treatment, it is important that we better understand its underlying processes. Our studies implicate a critical cytokine called interleukin-ip (IL-1P) as a factor that accelerates AD pathology. Here we propose to study the molecular mechanisms by which this cytokine alters basic cell biological functions and how these changes affect AD pathogenesis.